Skin Barrier Development Depends on CGI-58 Protein Expression during Late-Stage Keratinocyte Differentiation Susanne Grond, Franz P.W. Radner, Thomas.

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Skin Barrier Development Depends on CGI-58 Protein Expression during Late-Stage Keratinocyte Differentiation Susanne Grond, Franz P.W. Radner, Thomas O. Eichmann, Dagmar Kolb, Gernot F. Grabner, Heimo Wolinski, Robert Gruber, Peter Hofer, Christoph Heier, Silvia Schauer, Thomas Rülicke, Gerald Hoefler, Matthias Schmuth, Peter M. Elias, Achim Lass, Rudolf Zechner, Guenter Haemmerle Journal of Investigative Dermatology Volume 137, Issue 2, Pages 403-413 (February 2017) DOI: 10.1016/j.jid.2016.09.025 Copyright © 2016 The Authors Terms and Conditions

Figure 1 Defective skin permeability barrier and ichthyosis in Cgi-58epid−/− mice. (a) Phenotype, (b) body wet weight (n = 10), and (c) skin permeability barrier function analyzed by toluidine blue staining of newborn Cgi-58flox/flox and Cgi-58epid−/− mice. (d) Histology (hematoxylin and eosin staining; scale bar = 50 μm) and (e) transmission electron microscopy (TEM; scale bar = 1 μm) show hyperkeratosis, smaller F-granules, and lipid droplets (arrows) throughout the stratum corneum (SC) of Cgi-58epid−/− mice. (f) Impaired degradation of corneodesmosomes (arrows) in Cgi-58epid−/− mice as analyzed by TEM (scale bar = 1 μm). (g) Immunohistochemistry of desmoglein 1/2 (DSG1/2), (h) keratin 6 (K6), K14, and filaggrin (FLG) in skin sections of newborn Cgi-58flox/flox and Cgi-58epid−/− mice. Protein levels of (i) FLG or (j) loricrin (LOR) and involucrin (IVL) detected by western blot analysis using GAPDH (glyceraldehyde-3-phosphate dehydrogenase) as loading control. ***P < 0.001. CGI-58, comparative gene identification-58; SG, stratum granulosum. Journal of Investigative Dermatology 2017 137, 403-413DOI: (10.1016/j.jid.2016.09.025) Copyright © 2016 The Authors Terms and Conditions

Figure 2 Embryonic skin permeability barrier development in the absence of CGI-58. Skin permeability barrier function of Cgi-58epid−/− and Cgi-58flox/flox mice (a) assayed by toluidine blue staining between embryonic stages E15.5–E18.5, and (b) measured using a gravimetric TEWL assay at E16.5–E18.5, and P0. (c) CGI-58 and (d) filaggrin (FLG) protein levels analyzed by western blotting at indicated gestational ages in epidermal extracts of Cgi-58epid−/− and Cgi-58flox/flox mice (loading control = GAPDH). (e) Levels of covalently bound ω-hydroxy-ceramides (ω-OH-Cer) were determined by UPLC/MS in E16.5, E17.5, E18.5, and P0 epidermis from Cgi-58epid−/− and Cgi-58flox/flox mice (n = 4–6). (f) Body wet weight of Cgi-58epid−/− and Cgi-58flox/flox mice during late embryonic development (E15.5–E18.5) and shortly after birth (P0). Data are presented as means ± SD and are representative for two independent experiments. ***P < 0.001. CGI-58, comparative gene identification-58; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; MS, mass spectrometry; SD, standard deviation; TEWL, transepidermal water loss; UPLC, ultra performance liquid chromatography. Journal of Investigative Dermatology 2017 137, 403-413DOI: (10.1016/j.jid.2016.09.025) Copyright © 2016 The Authors Terms and Conditions

Figure 3 Restoration of CGI-58 expression in differentiated but not basal keratinocytes rescues the lethal skin barrier defect of Cgi-58−/− mice. Phenotypic characterization including gross appearance, skin permeability (assayed by toluidine blue penetration), and hematoxylin and eosin stain of skin sections (scale bar = 70 μm) of newborn (a–c) Cgi-58−/−/K14C and (d–f) Cgi-58−/−/IVLC mice compared with WT. (g) Phenotypes of 12-week-old female WT and Cgi-58−/−/IVLC mice. (h) Body wet weight and (i) body length of newborn WT and Cgi-58−/−/IVLC mice. CGI-58, comparative gene identification-58; K, keratin; WT, wild type. Journal of Investigative Dermatology 2017 137, 403-413DOI: (10.1016/j.jid.2016.09.025) Copyright © 2016 The Authors Terms and Conditions

Figure 4 Epidermal TG accumulation in the absence of CGI-58 involves impaired ATGL-mediated TG catabolism in the epidermis. (a) TG contents of epidermal lipid extracts derived from Cgi-58flox/flox, Cgi-58epid−/−, and Cgi-58−/−/IVLC mice were quantified by HPLC/LSD. Skin sections of newborn Cgi-58epid−/− mice show (b) lipid droplets (arrows) throughout the stratum corneum (SC) as analyzed by TEM (scale bar = 1 μm), and (c) numerous neutral lipid puncta as detected by label-free coherent anti-Stokes Raman scattering (CARS) microscopy (scale bar = 5 μm). Measurement of TG-hydrolase activities in epidermal preparations derived from (d) Cgi-58epid−/−, (e) Cgi-58−/−/IVLC, (f) Atgl−/− mice, and respective control mice (Cgi-58flox/flox and WT, respectively) in the absence and/or presence of recombinant CGI-58 and the ATGL-specific inhibitor Atglistatin (Ai), or a combination of both (n = pool of 4–7). Values represent means ± SD and are representative for three independent measurements. *P < 0.05; **P < 0.01; ***P < 0.001. ATGL, adipose triglyceride lipase; CGI-58, comparative gene identification-58; FA, fatty acid; LSD, light-scattering detection; SD, standard deviation; SG, stratum granulosum; TEM, transmission electron microscopy; TG, triglyceride; WT, wild type. Journal of Investigative Dermatology 2017 137, 403-413DOI: (10.1016/j.jid.2016.09.025) Copyright © 2016 The Authors Terms and Conditions

Figure 5 Defective ω-O-acylceramide and CLE formation caused by global CGI-58-deficiency is reversed on CGI-58 expression in the epidermis. (a) Compared with uniformly organized lamellar bilayers in Cgi-58flox/flox, bilayers show nonlamellar domains (arrows) in Cgi-58epid−/− mice. This can be ascribed to aberrant lamellar body (LB) internal structures (arrowheads), inhomogeneous LB secretion with entombed organelles in corneocytes (asterisks), and impaired postsecretory lipid processing (double arrows). TEM; ruthenium postfixation; scale bars = 100 nm. (b) Absent corneocyte lipid envelopes (arrows) and slightly thinner cornified envelopes (arrowheads) in Cgi-58epid−/− compared with Cgi-58flox/flox epidermis. TEM; pretreatment with pyridine; scale bar = 100 nm. Lipid analyses were performed by HPLC/LSD (cholesterol) or UPLC/MS (FA, ceramides) of indicated epidermal lipid extracts. Levels of (c) cholesterol, FA, CerNS, and ω-O-(18:2)-AcylCer, of (d) ω-O-(18:2)AcylGlcCer, and of (e) covalently bound ω-OH-Cer and FA in Cgi-58epid−/− and Cgi-58flox/flox epidermis. (f) ω-O-(18:2)-AcylCer, ω-O-(18:2)AcylGlcCer, and covalently bound ω-OH-Cer levels in WT, Cgi-58−/−, Cgi-58−/−/IVLC, and WT/IVLC epidermis. (g) Levels of free ω-OH-Cer and their glucosylated derivatives in Cgi-58epid−/− and Cgi-58flox/flox epidermis. Values represent means ± SD (n = 5) and are representative for three independent measurements. *P < 0.05; ***P < 0.001. CGI-58, comparative gene identification-58; CLE, corneocyte lipid envelope; F, F-granule; FA, fatty acid; LSD, light-scattering detection; MS, mass spectrometry; N, nucleus; ω-O-(18:2)AcylGlcCer, glucosylated ω-O-AcylCeramide; ω-OH-Cer, ω-hydroxy-ceramides; SD, standard deviation; TEM, transmission electron microscopy; UPLC, ultra performance liquid chromatography; WT, wild type. Journal of Investigative Dermatology 2017 137, 403-413DOI: (10.1016/j.jid.2016.09.025) Copyright © 2016 The Authors Terms and Conditions